Process for the production of sclareolide

ABSTRACT

A process for the production of sclareolide comprising the steps of: (1) providing an aqueous composition comprised of: (a) water; (b) sclareol, abienol, or a mixture of sclareol and abienol, (c) an effective amount of a ruthenium catalyst; and, (d) an emulsifying agent; (2) forming an aqueous alkaline composition by adding an alkali metal hydroxide to said aqueous composition; (3) reacting said aqueous alkaline composition with an oxidizing agent to form a crude product; and 
     either: (4) further reacting said crude product with base to form the salt of 8α-hydroxy-11-carboxyl-12, 13, 14, 15, 16-pentanorlabdane and; (5) reacting said salt with acid to form sclareolide; 
     or: (4) heating said crude product to form sclareolide.

This application is a 371 of PCT/EP93/00874 filed Apr. 8, 1993.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for the production of sclareolidefrom sclareol and/or abienol.

A full definition of the trivial names and abbreviations used in thefollowing in conjunction with the accompanying numbers in round bracketsis given in the Example section which shows the associated IUPAC nameand the corresponding structural formula.

2. Statement of the Related Art

Ambroxan (7) is a valuable ambergris fragrance which is found in ametabolic secretion of the sperm whale (cf. Ullmanns Enzyklopadie dertechnischen Chemic, Vol. 20, pages 283, Weinheim 1981). In view oflimited natural resources, the increasing demand for ambroxan has led inrecent years to the development of processes by which ambroxan can besynthetically obtained from inexpensive raw materials. Sclareolide (6)in particular has proved to be an important ambroxan precursor so thatthe concern of many research groups has been to develop processes bywhich sclareolide can be synthesized from natural raw materials, moreparticularly sclareol (1).

According to U.S. Pat. No. 3,050,532, sclareol is first oxidized withpotassium permanganate under alkaline reaction conditions to form thehydroxyketone (3) which, without further isolation, is converted withglacial acetic acid into the enolethers (4). The enolether is thenoxidized either with potassium permanganate or with chromic acid. Theoxidation product obtained is saponified and then cyclized to formsclareolide (6). Unfortunately, this process is attended by thedisadvantage that the oxidation step is carried out with potassiumpermanganate which is ecologically unsafe, i.e. toxic. In addition, theMnO₂ (magnesium dioxide) formed therefrom is very difficult to filteroff in the working-up phase.

Finally, German patent application DE 39 42 358 describes a process inwhich sclareol is first oxidatively degraded with hypochlorite salts inthe presence of ruthenium salts to form the hydroxyketone (3) and/or theenolether (4), the intermediate product thus obtained and isolated isoxidized with peracids and/or peracid salts and, after saponificationand acidic ring closure, is converted into sclareolide. This processgives sclareolide in a yield of around 65%, based on sclareol.

Accordingly, in view of the key position of ambroxan in the field offragrances, there is a general need to develop improved syntheses. Thisdemand extends in particular to improvements in individual process stepsand to the development of alternative syntheses for the production ofimportant intermediate products or precursors of ambroxan. Accordingly,the problem addressed by the present invention was to create betteraccess to sclareolide starting out from sclareol and structurallyclosely related compounds.

DESCRIPTION OF THE INVENTION

According to the invention, the solution to this problem characterizedin that sclareol (1) and abienol (2) is first reacted with 10.5 to 25times the molar quantity of an oxidizing agent in aqueous medium in theabsence of an organic solvent and in the presence of a rutheniumcatalyst and an emulsifier to form a crude product which, thereafter, iseither converted in the presence of a base into the salt of8α-hydroxy-11-carboxy-12,13,14,15,16-pentanorlabdane, hereinafterreferred to as the hydroxy acid (5), and the hydroxy acid (5) iscyclized in acidic medium to form sclareolide or is subjected to anafter-reaction at elevated temperature and subsequently distilled, theafter-reaction optionally taking place in situ during the distillationphase.

Accordingly, the present invention relates to a process for theproduction of sclareolide in which sclareol and/or abienol is reactedwith 10.5 to 25 times the molar quantity--based on sclareol and/orabienol--of an oxidizing agent in aqueous medium in the absence of anorganic solvent and in the presence of a ruthenium catalyst and anemulsifier to form a crude product which, thereafter, is either

(i) converted in the presence of a base into the salt of8α-hydroxy-11-carboxy-12,13,14,15,16-pentanorlabdane which is thencyclized in acidic medium to form sclareolide or

(ii) is subjected to an after-reaction at elevated temperature andsubsequently distilled, the after-reaction optionally taking place insitu during the distillation phase.

The advantage of the process according to the invention is that only asingle oxidation step is required and sclareol can be obtained in highyields. In addition, the oxidation step takes place in the absence of anorganic solvent in contrast to the cited prior art. Finally, embodiment(ii) represents another advantageous form of the process in whichcertain process steps of embodiment (i) can be eliminated.

The oxidizing agent is used in a 10.5 to 25 molar excess, based onsclareol and/or abienol. A 12- to 16-fold excess is particularlypreferred. Suitable oxidizing agents are, for example, peracids,hydrogen peroxide or alkali metal or alkaline earth metal hypochlorites.It has proved to be particularly favorable to use oxidizing agents inthe form of aqueous solutions. A particularly suitable oxidizing agentis sodium hypochlorite.

There are no particular restrictions on the type of emulsifier used,although nonionic surfactants and in particular adducts of ethyleneand/or propylene oxide with fatty alcohols or oxoalcohols have proved tobe particularly favorable. It is of particular advantage to use anadduct of 20 moles of ethylene oxide with commercial tallow alcohol.

In order to shorten the reaction time, it has been found to be ofadvantage to expose the reaction mixture--which is present in the formof an aqueous dispersion--before the actual reaction to conditions whichpromote the formation of a particularly fine-particle dispersion. Suchconditions include, for example, the application of ultrasound, the useof a high-speed shearing stirrer or a homogenizer, for example of theSupratron or Cavitron type.

The process is carried out at temperatures of 15° to 70° C. andpreferably at temperatures of 20° to 50° C.

The ruthenium catalyst is used in a quantity of 0.1 to 5 mole-% andpreferably in a quantity of 0.1 to 1.0 mole-%, based on sclareol and/orabienol. The ruthenium catalyst may consist both of elemental ruthenium,which may be used in the form of a powder or on a solid support, forexample active carbon or aluminium oxide, and of hydrated ruthenium(IV)oxide (RuO₂.nH₂ O) and ruthenium salts. Ruthenium trichloride (RuCl₃)has proved to be particularly suitable.

The process according to the invention is generally carried out asfollows: sclareol and/or abienol and the emulsifier are initiallyintroduced into water, an alkaline pH is if necessary adjusted byaddition of alkali metal hydroxide and the ruthenium catalyst is added.The oxidizing agent is then introduced. A crude product mixturepredominantly containing sclareolide and also secondary products isobtained. This crude product mixture is subsequently processed by one ofthe following variants:

(i) After the further addition of a base and heating, the secondaryproducts are converted into the corresponding salt of the hydroxy acid(5); in this process, sclareolide is also converted by ring opening intothe hydroxy acid (5). In a final step, the hydroxy acid (5) formed fromthe salt by acidification is cyclized in known manner by elimination ofwater to form sclareolide.

(ii) The crude product obtained in the oxidation step is heated underspecial conditions so that the secondary products mentioned can beconverted into sclareolide without any additional processing steps. Thismay be done, for example, by initially heating the crude product forabout 3 hours at temperatures of around 120° C.; the sclareolide is thendistilled off under moderate conditions, for example using a thin-layerevaporator. On the other hand, conversion into sclareolide may becarried out in situ by distilling the crude product at temperatureswhich, on the one hand, are high enough to promote conversion of thesecondary products into sclareolide, but which on the other hand aresufficiently moderate largely to avoid decomposition of the sclareolide.This may be achieved for example by distillation in a high vacuum at atemperature of around 140° C.

The following Examples are intended to illustrate the invention withoutlimiting it in any way.

EXAMPLES

1. Trivial names/abbreviations

    ______________________________________                                        Sclareol (1):                                                                 8α,13-Dihydroxy-14,15- didehydrolabdane                                                  ##STR1##                                                     Abienol (2):                                                                  8α-Hydroxy-12,13-didehydro- 14,15-didehydrolabdane [the Z or E          configuration may be present for the double bond between the atoms C-12       and C-13]                                                                                      ##STR2##                                                     Hydroxyketone (3):                                                            8α-Hydroxy-13-oxido-15,16- dinorlabdane                                                  ##STR3##                                                     Enolether (4):                                                                8α,13-Oxido-12,13-dehydro- 15,16-dinorlabdane                                            ##STR4##                                                     Hydroxy acid (5):                                                             8α-Hydroxy-11-carboxy- 12,13,14,15,16- pentanorlabdane                                   ##STR5##                                                     Sclareolide (6):                                                              8α,12-Oxido-12-oxo-13,14,15, 16-tetranorlabdane                                          ##STR6##                                                     Ambroxan (7):                                                                 8α,12-Oxido-13,14,15,16- tetranorlabdane                                                 ##STR7##                                                     ______________________________________                                    

2. Production Examples

In the following, all percentages (except for yields) are percentages byweight.

Examples 1 and 2 illustrate variant (i) [oxidation of sclareol to crudesclareolide, subsequent conversion of the secondary products presenttherein into the hydroxy acid and subsequent cyclization of the hydroxyacid to sclareolide], Example 2 showing the advantages of using aparticularly fine-particle dispersion.

Example 3 illustrates variant (ii) [oxidation of sclareol to crudesclareolide and its after-reaction in situ during the followingdistillation step].

EXAMPLE 1

(I) 62 g of sclareol and 1.9 g of an adduct of 20 moles of ethyleneoxide with tallow fatty alcohol ("Dehydol TA 20", a product of HenkelKGaA, Dusseldorf) were introduced into 350 ml of water and heated withstirring to 80° C. The dispersion was left to cool to 35°-40° C., afterwhich 0.83 g of ruthenium trichloride (25% solution, a product ofDegussa AG) and 112.5 g of a 50% aqueous KOH solution were added.1,862.5 g of a 13% aqueous sodium hypochlorite solution were thenintroduced with stirring over a period of 3 hours. After the NaOCl hadbeen added, the reaction mixture was stirred overnight, cooling to roomtemperature in the process.

(II) For working up, the mixture was adjusted to a pH value of 1-2 with150 ml of 40% sulfuric acid and the aqueous phase was separated off. Theorganic phase was taken up in 600 ml of toluene and washed twice with250 ml of water.

(III) 27.5 g of a 50% NaOH solution and 2.8 g of tetrabutylammoniumchloride were then added to the organic solution, after which thereaction mixture was stirred for 5 hours at 60° to 65° C. The reactionmixture was diluted with 500 ml of water, heated to 70° C. and theorganic phase was separated off. The aqueous phase was adjusted to a pHvalue of 2 with 40% sulfuric acid and extracted with 300 ml of toluene.

(IV) The toluene solution was heated under reflux for 4-5 hours on awater separator. After the solvent had been distilled off, sclareolidewas obtained in a yield of 72.6% of the theoretical.

EXAMPLE 2

Example 1 was repeated using 4 g of an adduct of 20 moles of ethyleneoxide with sorbitan monooleate ("Disponil SMO 120", a product of HenkelKGaA, Dusseldorf) and 1.5 g of Dehydol TA 20 (see Example 1) asemulsifier. The dispersion formed was subsequently passed through aCavitron which shortened the reaction time to 5 hours. Sclareolide wasobtained in a yield of 75% of the theoretical.

EXAMPLE 3

Example 2 was repeated leaving out steps (III) and (IV). Instead, afteracidification and phase separation, the organic residue was not taken upin toluene in step (II), but was directly distilled in a high vacuum(0.01 mbar) at 150° C. Sclareolide was obtained in a yield of 78% of thetheoretical.

We claim:
 1. A process for the production of sclareolide comprising thesteps of: (1) providing an aqueous composition comprised of: (a) water;(b) sclareol, abienol, or a mixture of sclareol and abienol, (c) aneffective amount of a ruthenium catalyst; and, (d) an emulsifying agent;(2) forming an aqueous alkaline composition by adding an alkali metalhydroxide to said aqueous composition; (3) reacting said aqueousalkaline composition with an oxidizing agent to form a crude product;(4) further reacting said crude product with base to form the salt of8α-hydroxy-11-carboxy-12,13, 14, 15, 16-pentanorlabdane; and (5)reacting said salt with acid to form sclareolide.
 2. The process ofclaim 1 wherein said oxidizing agent is selected from the groupconsisting of a peracid, hydrogen peroxide, an alkali metalhypochlorite, and an alkaline earth metal hypochlorite.
 3. The processof claim 1 wherein said oxidizing agent is sodium hypochlorite.
 4. Theprocess of claim 1 wherein said emulsifying agent is a nonionicsurfactant.
 5. The process of claim 4 wherein said nonionic surfactantis an adduct of 20 moles of ethylene oxide and commercial tallowalcohol.
 6. The process of claim 1 wherein step (3) is carried out at atemperature of from about 15° C. to about 70° C.
 7. The process of claim1 wherein said ruthenium catalyst is used in an amount equal to fromabout 0.1 to about 5.0 mole percent based on the amount of sclareol orabienol.
 8. The process of claim 1 wherein said ruthenium catalyst isRuCl₃.
 9. The process of claim 7 wherein said ruthenium catalyst isRuCl₃.
 10. The process of claim 1 wherein said aqueous alkalinecomposition is formed into a fine particle dispersion prior to step (3).11. A process for the production of sclareolide comprising the steps of:(1) providing an aqueous composition comprised of: (a) water; (b)sclareol, abienol, or a mixture of sclareol and abienoi, (c) aneffective amount of a ruthenium catalyst; and, (d) an emulsifying agent;(2) forming an aqueous alkaline composition by adding an alkali metalhydroxide to said aqueous composition; (3) reacting said aqueousalkaline composition with an oxidizing agent to form a crude product;and (4) heating said crude product to form sclareolide.
 12. The processof claim 11 wherein said oxidizing agent is selected from the groupconsisting of a peracid, hydrogen peroxide, an alkali metalhypochlorite, and an alkaline earth metal hypochlorite.
 13. The processof claim 11 wherein said oxidizing agent is sodium hypochlorite.
 14. Theprocess of claim 11 wherein said emulsifying agent is a nonionicsurfactant.
 15. The process of claim 14 wherein said nonionic suffactantis an adduct of 20 moles of ethylene oxide and commercial tallowalcohol.
 16. The process of claim 11 wherein step (3) is carried out ata temperature of from about 15° C. to about 70° C.
 17. The process ofclaim 11 wherein said ruthenium catalyst is used in an amount equal tofrom about 0.1 to about 5.0 mole percent based on the amount of sclareolor abienol.
 18. The process of claim 11 wherein said ruthenium catalystis RuCl₃.
 19. The process of claim 17 wherein said ruthenium catalyst isRuCl₃.
 20. The process of claim 11 wherein said aqueous alkalinecomposition is formed into a fine particle dispersion prior to step (3).